Selective and non-invasive visualization or treatment of vasculature

Abstract

Disclosed are methods and materials for visualizing or treating vasculature. The methods and materials in this invention relate to selective and non-invasive visualization, or treatment such as chemical occlusion, of vasculature in the mammalian eye. The methods utilize fluorescent dyes and tissue-reactive substances encapsulated within heat-sensitive liposomes which are subsequently heated to release the contents thereof at a pre-determined anatomical locus. The methods of this invention further utilize tissue-reactive agents which, when activated, are effective to cause localized tissue damage and occlusion of blood vessels and/or blood sinuses. The materials of this invention relate to diagnostic reagents and kits for visualizing or treating a mammalian blood vessel or sinus.

What is claimed is: 
     
       1. A method of occluding vasculature in a mammalian eye, comprising the steps of: (a) co-administering intravenously to a mammal a fluorescent dye encapsulated within heat-sensitive liposomes, a tissue-reactive agent activated by irradiation and a tissue-specific factor, said tissue-specific factor effective to impair growth or regeneration of a blood vessel or blood sinus;   (b) selectively heating vasculature at a pre-determined anatomical locus within the eye such that the heat-sensitive liposomes present at said locus release locally their contents wherein said tissue-reactive agent remains inactive;   (c) monitoring clearance of said fluorescent dye from vasculature at said locus with normal blood flow, while simultaneously monitoring and visualizing persistence of said fluorescent dye within vasculature at said locus having subnormal blood flow; and, after having visualized persistent fluorescence in said vasculature having subnormal blood flow,   (d) activating the tissue-reactive agent present in said vasculature having subnormal blood flow, such that the activated agent chemically occludes said vasculature.   
     
     
       2. The method of claim 1 wherein said tissue-specific factor comprises a factor effective to cause regression of a blood vessel or blood sinus. 
     
     
       3. The method of claim 1 wherein said tissue-specific factor comprises a factor which binds to endothelial cell receptors of a growing or regenerating blood vessel or blood sinus. 
     
     
       4. The method of claim 1 wherein said tissue-specific factor effective to impair growth or regeneration is an antibody. 
     
     
       5. The method of claim 4 wherein said antibody is an antibody against vascular endothelial growth factor. 
     
     
       6. The method of claim 4 wherein said antibody is an antibody against fibroblast growth factor. 
     
     
       7. The method of claim 1 wherein step (a) further comprises co-administering an anti-inflammatory agent encapsulated within heat-sensitive liposomes. 
     
     
       8. The method of claim 1 wherein step (a) further comprises co-administering an antibiotic encapsulated within heat-sensitive liposomes. 
     
     
       9. The method of claim 8 wherein the antibiotic is an anti-bacterial, anti-fungal, anti-neoplastic or anti-parasitic antibiotic. 
     
     
       10. A method of chemically occluding a blood vessel or blood sinus in a mammalian eye, comprising the steps of: (a) co-administering intravenously to a mammal a fluorescent dye and a tissue-specific factor, said dye and said factor being encapsulated within heat-sensitive liposomes, said factor effective to impair growth or regeneration of vasculature;   (b) non-invasively heating tissue at a pre-determined anatomical locus within the eye of said mammal comprising a blood vessel or sinus, thereby to lyse said heat-sensitive liposomes containing said fluorescent dye and to release the contents thereof at said locus;   (c) exciting said fluorescent dye;   (d) monitoring clearance of said fluorescent dye from a blood vessel or sinus at said locus with normal blood flow, while simultaneously monitoring and visualizing persistence of said fluorescent dye within a blood vessel or sinus at said locus having subnormal blood flow; and, after having visualized persistent fluorescence in said blood vessel or sinus blood flow,   (e) exposing said blood vessel or sinus at said locus to said tissue-specific factor disposed within said blood vessel or sinus, thereby to impair growth or regeneration sufficient to occlude said blood vessel or sinus.   
     
     
       11. The method of claim 10 wherein said tissue-specific factor comprises a factor effective to cause regression of a blood vessel or blood sinus. 
     
     
       12. The method of claim 10 wherein said tissue-specific factor comprises a factor which binds to endothelial cell receptors of a growing or regenerating blood vessel or blood sinus. 
     
     
       13. The method of claim 10 wherein said tissue-specific factor effective to impair growth or regeneration is an antibody. 
     
     
       14. The method of claim 13 wherein said antibody is an antibody against vascular endothelial growth factor. 
     
     
       15. The method of claim 13 wherein said antibody is an antibody against fibroblast growth factor. 
     
     
       16. The method of claim 10 wherein step (a) further comprises co-administering an anti-inflammatory agent encapsulated within heat-sensitive liposomes. 
     
     
       17. The method of claim 10 wherein step (a) further comprises co-administering an antibiotic encapsulated within heat-sensitive liposomes. 
     
     
       18. The method of claim 17 wherein the antibiotic is an anti-bacterial, anti-fungal, anti-neoplastic or anti-parasitic antibiotic. 
     
     
       19. A method of occluding vasculature in a mammalian eye comprising the steps of: (a) administering heat-sensitive liposomes intravenously to said mammal, said liposomes having a fluorescent dye encapsulated therein;   (b) irradiating a pre-determined anatomical locus within the eye with a first laser beam, said first beam selectively and non-invasively heating the vasculature at said pre-determined anatomical locus such that the heat-sensitive liposomes accumulated at said locus are lysed and said fluorescent dye is released into the vasculature at said locus;   (c) identifying a blood flow origin within said vasculature by visualizing an advancing blood/dye boundary within a feeder blood vessel that supplies blood to a vascular abnormality; and,   (d) occluding said feeder blood vessel with a second laser beam focused on said blood/dye boundary.   
     
     
       20. The method of claim 19 wherein said second beam is effective to cause heat damage to said feeder blood vessel such that said feeder blood vessel is coagulated and thereby occluded. 
     
     
       21. The method of claim 19 wherein said second beam is effective to activate said fluorescent dye such that tissue-reactive by-products are produced therefrom and said feeder blood vessel is thereby occluded. 
     
     
       22. A method of chemically occluding abnormal vasculature in a mammalian eye comprising the steps of: (a) administering heat-sensitive liposomes intravenously to said mammal, said liposomes having a tissue-reactive agent and a fluorescent dye encapsulated therein;   (b) irradiating a pre-determined anatomical locus within the eye with a first laser beam, said first beam selectively and non-invasively heating vasculature at said pre-determined anatomical locus such that the heat-sensitive liposomes accumulated at said locus are lysed and said tissue-reactive fluorescent dye is released into the vasculature at said locus;   (c) monitoring clearance of said fluorescent dye from vasculature at said locus with normal blood flow while simultaneously monitoring and visualizing persistence of said dye within vasculature at said locus with subnormal blood flow; and after having visualized persistent fluorescence in said vasculature having subnormal blood flow,   (d) irradiating with a second laser beam said vasculature with subnormal blood flow by focusing said second laser beam on vasculature containing persistent fluorescent dye, said second beam activating the tissue-reactive fluorescent dye persisting in said vasculature such that said vasculature are chemically damaged and thereby occluded.   
     
     
       23. The method of claim 22 wherein said fluorescent dye is said tissue-reactive agent.